Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA182361 | ENA |
REPOSITORIES: ENA
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Project description:An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8+ T cells, the mice, like human PDA patients, did not respond to two immunological checkpoint antagonists that promote the function of T cells, α-CTLA-4 and α-PD-L1. Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express Fibroblast Activation Protein (FAP). The depletion of the FAP+ stromal cell also uncovered the anti-tumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T cell checkpoint antagonists. Three findings suggested that CXCL12 explained the overriding immunosuppression by the FAP+ cell: T cells were absent from regions of the tumor containing cancer cells; cancer cells were coated with the chemokine, CXCL12; and the FAP+ CAF was the principle source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor (CXCR4) inhibitor, induced rapid T cell accumulation among cancer cells, and acted synergistically with α-PD-L1 to selectively and greatly diminish cancer cells, identified by their loss-of-heterozygosity (LOH) of Trp53. The residual tumor was comprised only of pre-malignant epithelial cells and inflammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP+ CAF, may direct tumor immune evasion in a model of human PDA.
2012-11-30 | GSE42605 | GEO
Project description:Tumors expressing high level of programmed cell death-1 (PD-1) ligand 1 (PD-L1) are more likely to respond to immune checkpoint blockers (ICBs) targeting PD-1 or PD-L1. However, more than half of tumor patients with high PD-L1 expression does not respond to ICBs and the underlying mechanisms are yet to be clarified. Here we show that depletion of developmentally regulated GTP-binding protein 2 (DRG2) inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 level in melanoma cells. DRG2-depleted cells showed decreased binding with recombinant PD-1. Although DRG2-depleted cells expressed high levels of PD-L1, anti-PD-1 ICB did not activate T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis of melanoma patients under anti-PD-1 treatment revealed that patients bearing tumors with high DRG2 protein level were more sensitive to PD-1 anti-PD-1 ICBs. These findings identify DRG2 as a regulator of recycling of endosomal PD-L1 and a key determinant for response to anti-PD-1 ICB and provide insights into how to increase the correlation between PD-L1 expression and response to ICB.
2023-11-06 | GSE231973 | GEO
Project description:Tumors expressing high level of programmed cell death-1 (PD-1) ligand 1 (PD-L1) are more likely to respond to immune checkpoint blockers (ICBs) targeting PD-1 or PD-L1. However, more than half of tumor patients with high PD-L1 expression does not respond to ICBs and the underlying mechanisms are yet to be clarified. Here we show that depletion of developmentally regulated GTP-binding protein 2 (DRG2) inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 level in melanoma cells. DRG2-depleted cells showed decreased binding with recombinant PD-1. Although DRG2-depleted cells expressed high levels of PD-L1, anti-PD-1 ICB did not activate T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis of melanoma patients under anti-PD-1 treatment revealed that patients bearing tumors with high DRG2 protein level were more sensitive to PD-1 anti-PD-1 ICBs. These findings identify DRG2 as a regulator of recycling of endosomal PD-L1 and a key determinant for response to anti-PD-1 ICB and provide insights into how to increase the correlation between PD-L1 expression and response to ICB.
2023-11-06 | GSE231972 | GEO
Project description:Antibodies and derivative drugs targeting immune checkpoints have been approved for the treatment of several malignancies, but there are fewer responses in patients with pancreatic cancer. Here, we designed a nanobody molecule with bi-targeting on PD-L1 and CXCR4, as both targets are overexpressed in many cancer cells and play important roles in tumorigenesis. The nanobody sequences targeting PD-L1 and CXCR4 were linked by the (G4S)3 flexible peptide to construct the anti-PD-L1/CXCR4 bispecific nanobody. The bispecific nanobody was expressed in E. coli cells and purified by affinity chromatography. The purified nanobody was biochemically characterized by mass spectrometry, Western blotting and flow cytometry to confirm the molecule and its association with both PD-L1 and CXCR4. The biological function of the nanobody and its anti-tumour effects were examined.
2023-03-11 | PXD037102 | Pride
Project description:New therapeutics targeting immune checkpoint proteins have significantly advanced treatment of non-small cell lung cancer (NSCLC), but protein level quantitation of drug targets presents a critical problem. We used multiplexed, targeted mass spectrometry (MS) to quantify the immunotherapy target proteins PD-1, PD-L1, PD-L2, IDO1, LAG3, TIM-3, VISTA, GITR, and CD40 in formalin-fixed, paraffin-embedded (FFPE) NSCLC specimens. Immunohistochemistry (IHC) and MS measurements for PD-L1 were weakly correlated, but IHC did not distinguish protein abundance differences detected by MS. PD-L2 abundance exceeded PD-L1 in over half the specimens and the drug target proteins all displayed different abundance patterns. mRNA correlated with protein abundance only for PD-1, PD-L1, and IDO1 and tumor mutation burden did not predict abundance of any protein targets. Global proteome analyses identified distinct proteotypes associated with high PD-L1-expressing and high IDO1-expressing NSCLC. MS quantification of multiple drug targets and tissue proteotypes can improve clinical evaluation of immunotherapies for NSCLC.
2020-06-22 | PXD019061 | panorama
Project description:Immune checkpoint inhibitors (ICIs) represented by anti-PD-1/PD-L1 antibodies have been widely applied for various cancers and the response rate to ICIs is closely associated with the tumor immune microenvironment (TIME). Here, we show that combinational targeting CCL7 and Fms-like tyrosine kinase 3 ligand (Flt3L) increases the infiltration and expansion of conventional type 1 dendritic cells (cDC1s) in tumor sites and enhances the T cell antitumor responses and the efficacy of anti-PD-1 therapy in subcutaneous tumor models and spontaneous KrasG12D non-small cell lung cancer (NSCLC) models. We demonstrate that the fusion protein PD-1Ab7 in which CCL7 is fused with the single chain fragment variable region of anti-PD-1 antibody (PD-1Ab) exhibits superior antitumor activities compared to PD-1Ab. Mechanistically, PD-1Ab7 promotes antitumor immunity by increasing the infiltration of cDC1s and the activation of T cells, which is severely compromised by depletion of Zbtb46+ cDCs or inhibition of the CCL7 receptor CCR2. Furthermore, complementation of Flt3L sensitizes the ICI-resistant tumors to PD-1Ab7 and synergizes with PD-1Ab7 to inhibit tumor progression. These findings highlight the essential roles of PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells for cancer prevention and provide therapeutic lead molecules for antitumor immunotherapy.
2023-02-18 | GSE225163 | GEO
Project description:Immune checkpoint inhibitors (ICIs) represented by anti-PD-1/PD-L1 antibodies have been widely applied for various cancers and the response rate to ICIs is closely associated with the tumor immune microenvironment (TIME). Here, we show that combinational targeting CCL7 and Fms-like tyrosine kinase 3 ligand (Flt3L) increases the infiltration and expansion of conventional type 1 dendritic cells (cDC1s) in tumor sites and enhances the T cell antitumor responses and the efficacy of anti-PD-1 therapy in subcutaneous tumor models and spontaneous KrasG12D non-small cell lung cancer (NSCLC) models. We demonstrate that the fusion protein PD-1Ab7 in which CCL7 is fused with the single chain fragment variable region of anti-PD-1 antibody (PD-1Ab) exhibits superior antitumor activities compared to PD-1Ab. Mechanistically, PD-1Ab7 promotes antitumor immunity by increasing the infiltration of cDC1s and the activation of T cells, which is severely compromised by depletion of Zbtb46+ cDCs or inhibition of the CCL7 receptor CCR2. Furthermore, complementation of Flt3L sensitizes the ICI-resistant tumors to PD-1Ab7 and synergizes with PD-1Ab7 to inhibit tumor progression. These findings highlight the essential roles of PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells for cancer prevention and provide therapeutic lead molecules for antitumor immunotherapy.
2023-02-18 | GSE225126 | GEO
Project description:Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell‑intrinsic functions in immune and cancer cells. In line with these studies, here we show that PD-L1 potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cells resulted in enhanced infection with oncolytic viruses in cancer cells in vitro and in vivo. PD-L1 expression marks tumor explants from cancer patients that are best infected by oncolytic viruses. Agonistic antibodies targeting PD-L1 further reduced type I IFN responses and enhanced oncolytic virus infection. Mechanistically, PD-L1 suppressed type I interferon by promoting Warburg metabolism, characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD‑L1‑expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
2023-06-28 | GSE210884 | GEO
Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
2022-10-27 | GSE209587 | GEO
Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
2022-10-27 | GSE208644 | GEO